Tri-and tetraaza-acenaphthylen derivatives as crf receptor antagonists

ABSTRACT

CRF receptor antagonists are disclosed which have utility in the treatment of a variety of disorders, including the treatment of disorders manifesting hypersecretion of CRF in a warm-blooded animals, such as stroke. The CRF receptor antagonists of this invention have the following structure of formula (I): including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof, R1, R2, R4, R5, R6, A, X, and Y are as defined herein. Compositions containing a CRF receptor antagonist in combination with a pharmaceutically acceptable carrier are also disclosed, as well as methods for use of the same.

TECHNICAL FIELD

[0001] This invention relates generally to CRF receptor antagonists, andto methods of treating disorders by administration of such antagoniststo a warm-blooded animal in need thereof.

BACKGROUND OF THE INVENTION

[0002] The first corticotropin-releasing factor (CRF) was isolated fromovine hypothalami and identified as a 41-amino acid peptide (Vale etal., Science 213:1394-1397, 1981). Subsequently, sequences of human andrat CRF were isolated and determined to be identical, but different fromovine CRF in 7 of the 41 amino acid residues (Rivier et al., Proc. Natl.Acad. Sci. USA 80:4851, 1983; Shibahara et al., EMBO J. 2:775, 1983).

[0003] CRF has been found to produce profound alterations in endocrine,nervous and immune system function. CRF is believed to be the majorphysiological regulator of the basal and stress-release ofadrenocorticotropic hormone (“ACTH”), β-endorphin, and otherpro-opiomelanocortin (“POMC”)-derived peptides from the anteriorpituitary (Vale et al., Science 213:1394-1397, 1981). Briefly, CRF isbelieved to initiate its biological effects by binding to a plasmamembrane receptor which has been found to be distributed throughout thebrain (DeSouza et al., Science 224:1449-1451, 1984), pituitary (DeSouzaet al., Methods Enzymol. 124:560, 1986; Wynn et al., Biochem. Biophys.Res. Comm. 110:602-608, 1983), adrenals (Udelsman et al., Nature319:147-150, 1986) and spleen (Webster, E. L., and E. S. DeSouza,Endocrinology 122:609-617, 1988) The CRF receptor is coupled to aGTP-binding protein (Perrin et al., Endocrinology 118:1171-1179, 1986)which mediates CRF-stimulated increase in intracellular production ofcAMP (Bilezikjian, L. M., and W. W. Vale, Endocrinology 113:657-662,1983). The receptor for CRF has now been cloned from rat (Perrin et al.,Endo 133(6):3058-3061, 1993), and human brain (Chen et al., PNAS90(19):8967-8971, 1993; Vita et al., FEBS 335(1):1-5, 1993). Thisreceptor is a 415 amino acid protein comprising seven membrane spanningdomains. A comparison of identity between rat and human sequences showsa high degree of homology (97%) at the amino acid level.

[0004] In addition to its role in stimulating the production of ACTH andPOMC, CRF is also believed to coordinate many of the endocrine,autonomic, and behavioral responses to stress, and may be involved inthe pathophysiology of affective disorders. Moreover, CRF is believed tobe a key intermediary in communication between the immune, centralnervous, endocrine and cardiovascular systems (Crofford et al., J. Clin.Invest. 90:2555-2564, 1992; Sapolsky et al., Science 238:522-524, 1987;Tilders et al., Regul. Peptides 5:77-84, 1982). Overall, CRF appears tobe one of the pivotal central nervous system neurotransmitters and playsa crucial role in integrating the body's overall response to stress.

[0005] Administration of CRF directly to the brain elicits behavioral,physiological, and endocrine responses identical to those observed foran animal exposed to a stressful environment. For example,intracerebroventricular injection of CRF results in behavioralactivation (Sutton et al., Nature 297:331, 1982), persistent activationof the electroencephalogram (Ehlers et al., Brain Res. 278:332, 1983),stimulation of the sympathoadrenomedullary pathway (Brown et al.,Endocrinology 110:928, 1982), an increase of heart rate and bloodpressure (Fisher et al., Endocrinology 110:2222, 1982), an increase inoxygen consumption (Brown et al., Life Sciences 30:207, 1982),alteration of gastrointestinal activity (Williams et al., Am. J.Physiol. 253:G582, 1987), suppression of food consumption (Levine etal., Neuropharmacology 22:337, 1983), modification of sexual behavior(Sirinathsinghji et al., Nature 305:232, 1983), and immune functioncompromise (Irwin et al., Am. J. Physiol. 255:R744, 1988).

[0006] Furthermore, clinical data suggests that CRF may be hypersecretedin the brain in depression, anxiety-related disorders, and anorexianervosa. (DeSouza, Ann. Reports in Med. Chem. 25:215-223, 1990).Accordingly, clinical data suggests that CRF receptor antagonists mayrepresent novel antidepressant and/or anxiolytic drugs that may beuseful in the treatment of the neuropsychiatric disorders manifestinghypersecretion of CRF.

[0007] The first CRF receptor antagonists were peptides (see, e.g.,Rivier et al., U.S. Pat. No. 4,605,642; Rivier et al., Science 224:889,1984). While these peptides established that CRF receptor antagonistscan attenuate the pharmacological responses to CRF, peptide CRF receptorantagonists suffer from the usual drawbacks of peptide therapeuticsincluding lack of stability and limited oral activity. More recently,small molecule CRF receptor antagonists have been reported. For example,substituted 4-thio-5-oxo-3-pyrazoline derivatives (Abreu et al., U.S.Pat. No. 5,063,245) and substituted 2-aminothiazole derivatives(Courtemanche et al., Australian Patent No. AU-A-41399/93) have beenreported as CRF receptor antagonists. These particular derivatives werefound to be effective in inhibiting the binding of CRF to its receptorin the 1-10 μM range and 0.1-10 μM range, respectively.

[0008] Due to the physiological significance of CRF, the development ofbiologically-active small molecules having significant CRF receptorbinding activity and which are capable of antagonizing the CRF receptorremains a desirable goal. Such CRF receptor antagonists would be usefulin the treatment of endocrine, psychiatric and neurologic conditions orillnesses, including stress-related disorders in general.

[0009] While significant strides have been made toward achieving CRFregulation through administration of CRF receptor antagonists, thereremains a need in the art for effective small molecule CRF receptorantagonists. There is also a need for pharmaceutical compositionscontaining such CRF receptor antagonists, as well as methods relating tothe use thereof to treat, for example, stress-related disorders. Thepresent invention fulfills these needs, and provides other relatedadvantages.

SUMMARY OF THE INVENTION

[0010] In brief, this invention is generally directed to CRF receptorantagonists, and more specifically to CRF receptor antagonists havingthe following general structure (I):

[0011] including stereoisomers, prodrugs and pharmaceutically acceptablesalts thereof, wherein R₁, R₂, R₄, R₅, R₆, A, X, and Y are as definedbelow.

[0012] The CRF receptor antagonists of this invention have utility overa wide range of therapeutic applications, and may be used to treat avariety of disorders or illnesses, including stress-related disorders.Such methods include administering an effective amount of a CRF receptorantagonist of this invention, preferably in the form of a pharmaceuticalcomposition, to an animal in need thereof Accordingly, in anotherembodiment, pharmaceutical compositions are disclosed containing one ormore CRF receptor antagonists of this invention in combination with apharmaceutically acceptable carrier and/or diluent.

[0013] These and other aspects of the invention will be apparent uponreference to the following detailed description. To this end, variousreferences are set forth herein which describe in more detail certainprocedures, compounds and/or compositions, and are hereby incorporatedby reference in their entirety.

DETAILED DESCRIPTION OF THE INVENTION

[0014] The present invention is directed generally to compounds usefulas corticotropin-releasing factor (CRF) receptor antagonists.

[0015] In a first embodiment, the CRF receptor antagonists of thisinvention have the following structure (I):

[0016] including stereoisomers, prodrugs and pharmaceutically acceptablesalts thereof, wherein:

[0017] A is a bond or C=(Z);

[0018] X is nitrogen or CR₃;

[0019] Y is —N═, —N(R₇)—, C(R₈)═ or —O—;

[0020] Z is O, S or NR₉;

[0021] R₁ is alkyl, substituted alkyl, aryl, substituted aryl,heteroaryl, or substituted heteroaryl;

[0022] R₂ is hydrogen, alkyl, substituted alkyl, alkoxy, thioalkyl,halo, cyano, haloalkyl;

[0023] R₃ is hydrogen, alkyl, substituted alkyl, halo or haloalkyl;

[0024] R₄ is hydrogen, alkyl, substituted alkyl, C(O)R₁, aryl,substituted aryl, heterocycle or substituted heterocycle;

[0025] R₅ is hydrogen, halogen, alkyl, substituted alkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, thioalkyl,C(O)R₁, NR₁₀R₁₁ or cyano;

[0026] R₆ is hydrogen, halogen, alkyl, substituted alkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, thioalkyl,C(O)R₁, NR₁₀R₁₁ or cyano;

[0027] R₇ is hydrogen, alkyl, substituted alkyl, C(O)R₁, aryl,substituted aryl, heteroaryl, or substituted heteroaryl;

[0028] R₈ is hydrogen, halogen, alkyl, substituted alkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, thioalkyl,C(O)alkyl, NR₁₀R₁₁ or cyano;

[0029] R₉ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl,heteroaryl, or substituted heteroaryl; and

[0030] R₁₀, R₁₁ are the same or different and are independentlyhydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl.

[0031] As used herein, the above terms have the following meaning:

[0032] “Alkyl” means a straight chain or branched, noncyclic or cyclic,unsaturated or saturated aliphatic hydrocarbon containing from 1 to 10carbon atoms, while the term “lower alkyl” has the same meaning as alkylbut contains from 1 to 6 carbon atoms. Representative saturated straightchain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl,n-hexyl, and the like; while saturated branched alkyls includeisopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, and the like.Representative saturated cyclic alkyls include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, —CH₂cyclopropyl, —CH₂cyclobutyl,—CH₂cyclopentyl, —CH₂cyclohexyl, and the like; while unsaturated cyclicalkyls include cyclopentenyl and cyclohexenyl, and the like. Cyclicalkyls, also referred to as “homocyclic rings,” and include di- andpoly-homocyclic rings such as decalin and adamantyl, Unsaturated alkylscontain at least one double or triple bond between adjacent carbon atoms(referred to as an “alkenyl” or “alkynyl”, respectively). Representativestraight chain and branched alkenyls include ethylenyl, propylenyl,1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl,3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, and thelike; while representative straight chain and branched alkynyls includeacetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl,3-methyl-1 butynyl, and the like.

[0033] “Aryl” means an aromatic carbocyclic moiety such as phenyl ornaphthyl.

[0034] “Arylalkyl” means an alkyl having at least one alkyl hydrogenatoms replaced with an aryl moiety, such as benzyl, —CH₂-(1 or2-naphthyl), —(CH₂)₂phenyl, —(CH₂)₃phenyl, —CH(phenyl)₂, and the like.

[0035] “Heteroaryl” means an aromatic heterocycle ring of 5- to 10members and having at least one heteroatom selected from nitrogen,oxygen and sulfur, and containing at least 1 carbon atom, including bothmono- and bicyclic ring systems. Representative heteroaryls include (butare not limited to) furyl, benzofuranyl, thiophenyl, benzothiophenyl,pyrrolyl, indolyl, isoindolyl, azaindolyl, pyridyl, quinolinyl,isoquinolinyl, oxazolyl, isooxazolyl, benzoxazolyl, pyrazolyl,imidazolyl, benzimidazolyl, thiazolyl, benzothiazolyl, isothiazolyl,pyridazinyl, pyrinidinyl, pyrazinyl, triazinyl, cinnolinyl,phthalazinyl, and quinazolinyl.

[0036] “Heteroarylalkyl” means an alkyl having at least one alkylhydrogen atom replaced with a heteroaryl moiety, such as —CH₂pyridinyl,—CH₂pyrimidinyl, and the like.

[0037] “Heterocycle” (also referred to herein as a “heterocycle ring”)means a 5- to 7-membered monocyclic, or 7- to 14-membered polycyclic,heterocycle ring which is either saturated, unsaturated or aromatic, andwhich contains from 1 to 4 heteroatoms independently selected fromnitrogen, oxygen and sulfur, and wherein the nitrogen and sulfurheteroatoms may be optionally oxidized, and the nitrogen heteroatom maybe optionally quaternized, including bicyclic rings in which any of theabove heterocycles are fused to a benzene ring as well as tricyclic (andhigher) heterocyclic rings. The heterocycle may be attached via anyheteroatom or carbon atom Heterocycles include heteroaryls as definedabove. Thus, in addition to the aromatic heteroaryls listed above,heterocycles also include (but are not limited to) morpholinyl,pyrrolidinonyl, pyrrolidinyl, piperidinyl, hydantoinyl, valerolactamyl,oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl,tetrrhydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl,tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetmhydrothiophenyl,tetrahydrothiopyranyl, and the like.

[0038] “Heterocyclealkyl” means an alkyl having at least one alkylhydrogen atom replaced with a heterocycle, such as —CH₂morpholinyl, andthe like.

[0039] “Cycloalkyl” means a saturated or unsaturated (but not aromatic)carbocyclic ring containing from 3-8 carbon atoms, such as cyclopentane,cyclohexane, cycloheptane, cyclohexene, and the like.

[0040] “Cycloalkylcycloalkyl” means a cycloalkyl ring fused to acycloalkyl ring, such as decalin.

[0041] “Cycloalkylaryl” means a cycloalkyl ring fused to aryl, such astetran.

[0042] “Cycloalkylheterocycle” means a cycloalkyl ring fused to aheterocycle ring.

[0043] The term “substituted” as used herein means any of the abovegroups (eg., alkyl, aryl, arylallyl, heteroaryl, heterdarylalkyl,heterocycle, heterocyclealkyl, etc.) wherein at least one hydrogen atomis replaced with a substituent. In the case of a keto substituent(“—C(═O)—”) two hydrogen atoms are replaced. When substituted,“substituents” within the context of this invention include halogen,hydroxy, cyano, nitro, amino, alkylamino, dialkylamino, alkyl, alkoxy,alkylthio, haloalkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, heteroaryl, substituted heteroaryl, heteroaxylalkyl,substituted heteroarylalkyl, heterocycle, substituted heterocycle,heterocyclealkyl, substituted heterocyclealkyl, —NR_(a)R_(b),—NR_(a)C(═O)R_(b), —NR_(a)C(═O)NR_(a)R_(b), —NR_(a)C(═O)OR_(b)—NR_(a)SO₂R_(b), —OR_(a), —C(═O)R_(a) —C(═O)OR_(a) —C(═O)NR_(a)R_(b),—OC(═O)NR_(a)R_(b), —SH, —SR_(a), —SOR_(a), —S(═O)₂R_(a), —OS(═O)₂R_(a),—S(═O)₂OR_(a), wherein R_(a) and R_(b) are the same or different andindependently hydrogen, alkyl, haloalkyl substituted allyl, aryl,substituted aryl arylalkyl, substituted arylalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl,heterocycle, substituted heterocycle, heterocyclealkyl or substitutedheterocyclealkyl.

[0044] “Halogen” means fluoro, chloro, bromo and iodo.

[0045] “Haloalkyl” means an alkyl having at least one hydrogen atomreplaced with halogen, such as trifluoromethyl and the like.

[0046] “Alkoxy” means an alkyl moiety attached through an oxygen bridge(i.e., —O-alkyl) such as methoxy, ethoxy, and the like.

[0047] “Alkylthio” means an alkyl moiety attached through a sulfurbridge (i.e., —S-alkyl) such as methylthio, ethylthio, and the like.

[0048] “Alkylsulfonyl” means an alkyl moiety attached through a sulfonylbridge (i.e., —SO₂-alkyl) such as methylsulfonyl, ethylsulfonyl, and thelike.

[0049] “Alkylamino” and “dialkylamino” mean one or two alkyl moietyattached through a nitrogen bridge (i.e., —N-alkyl) such as methylamino,ethylamino, dimethylamino, diethylamino, and the like.

[0050] “Hydroxyalkyl” means an alkyl substituted with at least onehydroxyl group. “Mono- or di(cycloalkyl)methyl” represents a methylgroup substituted with one or two cycloalkyl groups, such ascyclopropylmethyl, dicyclopropylmethyl, and the like.

[0051] “Alkylcarbonylalkyl” represents an alkyl substituted with a—C(═O)alkyl group.

[0052] “Alkylcarbonyloxyalkyl” represents an alkyl substituted with a—C(═O)Oalkyl group or a —OC(═O)alkyl group.

[0053] “Alkyloxyalkyl” represents an alkyl substituted with a —O-alkylgroup.

[0054] “Alkylthioalkyl” represents a alkyl substituted with a —S-alkylgroup.

[0055] “Mono- or di(alkyl)amino represents an amino substituted with onealkyl or with two alkyls, respectively.

[0056] “Mono- or di(alkyl)aminoalkyl” represents a alkyl substitutedwith a mono- or di(alkyl)amino.

[0057] Depending upon the A, X, Y substituents, representative compoundsof this invention include the following structure (II) through (XII):

[0058] In more specific embodiments of this invention, representative R₁groups of this invention include (but are not limited to)2,4-dichlorophenyl, 2,4-dimethyl-phenyl, 2-chloro-4-methylphenyl,2-methyl-4-chlorophenyl, 2,4,6-trimethylphenyl, 2-chloro-methoxyphenyl,2-methyl-4-methoxyphenyl, 2,4-dimethoxyphenyl,2-trifluoromethyl-4-chlorophenyl, 3-methoxy-4-chlorophenyl,2,5-dimethoxy-4-chlorophenyl, 2-methoxy-4-trichloromethylphenyl,2-methoxy-4-isopropylphenyl 2-methoxy-4-trifluoromethylphenyl,2-methoxy-4-isopropylphenyl 2-methoxy-4-methylphenyl,4-methyl-6-dimethylaminopyridin-3-yl,4-dimethylaino-6-methyl-pyridin-3-yl, 6-dimethylamino-pyridin-3-yl and4-diethylamino-pyridin-3-yl.

[0059] Similarly, representative R₂ groups include hydrogen and alkylsuch as methyl and ethyl, while representative R₃ groups includehydrogen, halogen such as chlorine, fluorine and bromine, alkyl such asmethyl and ethyl, orhaloalkyl such as trifluoromethyl.

[0060] Preferred compounds according to the invention are:

[0061]7-methyl-1-(1-propyl-butyl)-5-[4-1,1,2-trifluoro-ethyl)-2-trifluoromethylphenyl]1,2,2a,3,4,5-exahydro-1,5,6,8-tetraaza-acenaphtylene(5-1-1);

[0062]3-methyl-4-[7-methyl-1-(1-propyl-butyl)-3,4-dihydro-1H-1,5,6,8-tetraaza-acenaphthylen-5-yl]-benzonitrile(5-1-2);

[0063]4-[1-(1-ethyl-propyl)-7-methyl-3,4-dihydro-1H-1,5,6,8-tetraaza-acenaphthylen-5-yl]-3-methyl-benzonitrile(5-1-3);

[0064]3-chloro-4-[7-methyl-1-(1-propyl-butyl)-3,4-dihydro-1H-1,5,6,8-tetraaza-acenaphthylen-5-yl]-benzonitrile(5-1-4);

[0065]3-chloro-4-[1-(1-ethyl-propyl)-7-methyl-3,4-dihydro-1H-1,5,6,8-tetraaza-acenaphthylen-5-yl-benzonitrile(5-1-5);

[0066]5-(2,4-bis-trifluoromethyl-phenyl)-1(1-ethyl-propyl)-7-methyl-1,3,4,5-tetrahydro-1,5,6,8-tetraaza-acenaphthylene(5-1-6);

[0067]5-(2,4-bis-trifluoromethyl-phenyl)-7-methyl-1-(1-propyl-butyl)-1,3,4,5-tetrahydro-1,5,6-triaza-acenaphthylene(6-1-1).

[0068] The compounds of the present invention may generally be utilizedas the free base. Alternatively, the compounds of this invention may beused in the form of acid addition salts. Acid addition salts of the freebase amino compounds of the present invention may be prepared by methodswell known in the art, and may be formed from organic and inorganicacids.

[0069] Suitable organic acids include maleic, malic, fumaric, benzoic,ascorbic, succinic, methanesulfonic, p-toluensulfonic, acetic, oxalic,propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic,cinnamic, aspartic; stearic, palmitic, glycolic, glutamic, andbenzenesulfonic acids. Suitable inorganic acids include hydrochloric,hydrobromic, sulfuric, phosphoric, and nitric acids. Thus, the term“pharmaceutically acceptable salt” of structure (I) is intended toencompass any and all acceptable salt forms.

[0070] In general, the compounds of structure (I) may be made accordingto the organic synthesis techniques known to those skilled in thisfield, as well as by the representative methods set forth in theExamples.

[0071] In particular, compounds of formula (XIa) may be preparedaccording to the following Scheme 1, starting from compounds (XIII), inwhich the hydroxy group is conveniently protected with a suitableprotecting group (Pg), whose preparation is described in the followingExamples:

[0072] in which:

[0073] step a stands for oxidative cleavage of the double bond by, forexample, ozonization; followed by reductive wok-up;

[0074] step b stands for conversion of the hydroxy group in a leavinggroup, such as mesylate;

[0075] step c stands for alkylation with the suitable aniline derivativeR₁NH₂ in strong basic conditions, followed by a “in situ” intramolecularcyclisation;

[0076] step d stands for deprotection of the hydroxy protecting group(e.g. Et₃N—3HF in DMF at r.t. overnight);

[0077] step e stands for conversion of the hydroxy group in a leavinggroup, such as mesylate;

[0078] step f stands for reaction with the suitable amine R₄NH₂ byheating;

[0079] step g stands for dehydrogenation by oxidation with the suitableoxidating agent (e.g.DDQ).

[0080] The starting compounds (XIII) may be conveniently preparedaccording to the following Scheme 2:

[0081] in which

[0082] step a′ stands for reaction with the suitable amidine andintramolecular cyclisation in basic conditions (i.e. MeONa, refluxingtoluene);

[0083] step b′ stands for chlorination (in similar way to what describedin Wayne G. C. et al., J. Prakt. Chem., (2000), 342(5), 504-7);

[0084] step c′ stands for allylation with allyl iodide at 0° C. in basicconditions (e.g. LiHMDS);

[0085] step d′ stands for reduction of the ester group with a suitablereducing agent, e.g. DIBMAl—H, in usual conditions (CH₂Cl₂, 0° C. tor.t.);

[0086] step e′ stands for protection of the hydroxy group, preferablywith t-BuPh₂SiCl (TBP), in DMF with DMAP as catalyst (0° C. to r.t).

[0087] Compounds of formula (XIb) may be conveniently prepared accordingto the following Scheme 3, starting from compounds of formula (XXV):

[0088] in which:

[0089] step a″ stands for homologation of a carbon atom by Wittigreaction with the suitable ylide, in the presence of a suitable organicbase like n-BuLi. The reaction is carried out in an aprotic solvent suchas acetonitrile or an ether such as tetrahydrofuran;

[0090] step b″ stands for usual hydrolysis in acid conditions (e.g. HClin THF) of the enol ether (XXVI);

[0091] step c″ stands for reduction of the aldehyde group by a suitablereducing agent (e.g. NaBH₄);

[0092] step d″ stands for protection of the hydroxy, preferably witht-BuMe₂SiCl (TBS), in DMF with imidazole and DMAP as catalyst (0° C. tor.t);

[0093] step e″ stands for microwave assisted Buchwald reaction with thesuitable aniline derivative R₁NH₂;

[0094] step f″ stands for deprotection of the hydroxy protecting group(e.g. Et₃N—3HF in DMF at r.t. overnight);

[0095] step g″ stands for conversion of the hydroxy group in a leavinggroup, such as mesylate;

[0096] step h″ stands for intramolecular cyclisation in basicconditions.

[0097] Alternatively, the final compounds (XIb) may be obtained fromcompounds (XXXI) by intramolecular cyclisation, for example bymesylation of the hydroxy group in basic conditions (i.e. Et₃N) followedby in situ cyclisation (step i″).

[0098] In a preferred embodiment of the invention for the compounds(XIa) and (XIb), R₃, R₅, R₆ and R₈ are hydrogen.

[0099] Examples of suitable hydroxy protecting group includetrihydrocarbyl silyl ethers such as the trimethylsilyl ort-butyldimethylsilyl ether. The hydroxyl protecting groups may beremoved by well-known standard procedures (such as those described inProtective Groups in Organic Chemistry, pages 46-119, Edited by J F WMcOmie (Plenum Press, 1973)). For example when Rb is at-butyldimethylsilyl group, this may be removed by treatment withtriethylamine trihydrofluoride.

[0100] The subject invention also includes isotopically-labeledcompounds, which are identical to those recited in formulas I andfollowing, but for the fact that one or more atoms are replaced by anatom having an atomic mass or mass number different from the atomic massor mass number usually found in nature. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, andchlorine, such as ³H, ¹¹C, ¹⁴C, ¹⁸F, ¹²³I and ¹²⁵I. Compounds of thepresent invention and pharmaceutically acceptable salts of saidcompounds that contain the aforementioned isotopes and/or other isotopesof other atoms are within the scope of the present invention.Isotopically—labeled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H, ¹⁴C are incorporated,are useful in drug and/or substrate tissue distnbution assays.Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularlypreferred for their ease of preparation and detectability. ¹¹C and ⁸Fisotopes are particularly useful in PET (positron emission tomography),and ¹²⁵I are particularly useful in SPECT (single photon emissioncomputerized tomography), all useful in brain imaging. Further,substitution with heavier isotopes such as deuterium, i.e., ²H, canafford certain therapeutic advantages resulting from greater metabolicstability, for example increased in vivo half-life or reduced dosagerequirements and, hence, may be preferred in some circumstances.Isotopically labeled compounds of formula I and following of thisinvention can generally be prepared by carrying out the proceduresdisclosed in the Schemes and/or in the Examples below, by substituting areadily available isotopically labeled reagent for a non-isotopicallylabeled reagent.

[0101] The effectiveness of a compound as a CRF receptor antagonist maybe determined by various assay methods. Suitable CRF antagonists of thisinvention are capable of inhibiting the specific binding of CRF to itsreceptor and antagonizing activities associated with CRF. A compound ofstructure (I) may be assessed for activity as a CRF antagonist by one ormore generally accepted assays for this purpose, including (but notlimited to) the assays disclosed by DeSouza et al. (J. Neuroscience7:88, 1987) and Battaglia et al. (Synapse 1:572, 1987). As mentionedabove, suitable CRF antagonists include compounds which demonstrate CRFreceptor affinity. CRF receptor affinity may be determined by bindingstudies that measure the ability of a compound to inhibit the binding ofa radiolabeled CRF (eg., [¹²⁵I]tyrosine-CFR) to its receptor (e.g.,receptors prepared from rat cerebral cortex membranes). The radioligandbinding assay described by DeSouza et al. (supra, 1987) provides anassay for determining a compound's affinity for the CRF receptor. Suchactivity is typically calculated from the IC₅₀ as the concentration of acompound necessary to displace 50% of the radiolabeled ligand from thereceptor, and is reported as a “K_(i)” value calculated by the followingequation: $K_{i} = \frac{{IC}_{50}}{1 + {L/K_{D}}}$

[0102] where L=radioligand and K_(D)=affinity of radioligand forreceptor (Cheng and Prusoff, Biochem. Pharmacol. 22:3099, 1973).

[0103] In addition to inhibiting CRF receptor binding, a compound's CRFreceptor antagonist activity may be established by the ability of thecompound to antagonize an activity associated with CRF. For example, CRFis known to stimulate various biochemical processes, including adenylatecyclase activity. Therefore, compounds may be evaluated as CRFantagonists by their ability to antagonize CRF-stimulated adenylatecyclase activity by, for example, measuring cAMP levels. TheCRF-stimulated adenylate cyclase activity assay described by Battagliaet al. (supra, 1987) provides an assay for determining a compound'sability to antagonize CRF activity. Accordingly, CRF receptor antagonistactivity may be determined by assay techniques which generally includean initial binding assay (such as disclosed by DeSouza (supra, 1987))followed by a cAMP screening protocol (such as disclosed by Battaglia(supra, 1987)).

[0104] With reference to CRF receptor binding affinities, CRF receptorantagonists of this invention have a K_(i) of less than 10 μM. In apreferred embodiment of this invention, a CRF receptor antagonist has aK_(i) of less than 1 μM, and more preferably less than 0.25 μM (ie., 250nM). As set forth in greater detail below, the K_(i) values ofrepresentative compounds of this invention may be assayed by the methodsset forth in Example 7.

[0105] The CRF receptor antagonists of the present invention demonstrateactivity at the CRF receptor site, and may be used as therapeutic agentsfor the treatment of a wide range of disorders or illnesses includingendocrine, psychiatric, and neurologic disorders or illnesses. Morespecifically, the CRF receptor antagonists of the present invention maybe useful in treating physiological conditions or disorders arising fromthe hypersecretion of CRF. Because CRF is believed to be a pivotalneurotransmitter that activates and coordinates the endocrine,behavioral and automatic responses to stress, the CRF receptorantagonists of the present invention can be used to treatneuropsychiatric disorders. Neuropsychiatric disorders which may betreatable by the CRF receptor antagonists of this invention includeaffective disorders such as depression; anxiety-related disorders suchas generalized anxiety disorder, panic disorder, obsessive-compulsivedisorder, abnormal aggression, cardiovascular abnormalities such asunstable angina and reactive hypertension; and feeding disorders such asanorexia nervosa, bulimia, and irritable bowel syndrome (IBS). CRFantagonists may also be useful in treating stress-induced immunesuppression associated with various diseases states, as well as stroke.Other uses of the CRF antagonists of this invention include treatment ofinflammatory conditions (such as rheumatoid arthritis, uveitis, asthma,inflammatory bowel disease (IBD) and G.I. motility), Cushing's disease,infantile spasms, epilepsy and other seizures in both infants andadults, and various substance abuse and withdrawal (includingalcoholism).

[0106] In another embodiment of the invention, pharmaceuticalcompositions containing one or more CRF receptor antagonists aredisclosed. For the purposes of administration, the compounds of thepresent invention may be formulated as pharmaceutical compositions.Pharmaceutical compositions of the present invention comprise a CRFreceptor antagonist of the present invention (i.e., a compound ofstructure (I)) and a pharmaceutically acceptable carrier and/or diluent.The CRF receptor antagonist is present in the composition in an amountwhich is effective to treat a particular disorder—that is, in an amountsufficient to achieve CRF receptor antagonist activity, and preferablywith acceptable toxicity to the patient. Preferably, the pharmaceuticalcompositions of the present invention may include a CRF receptorantagonist in an amount from 0.1 mg to 250 mg per dosage depending uponthe route of administration, and more preferably from 1 mg to 60 mg.Appropriate concentrations and dosages can be readily determined by oneskilled in the art.

[0107] Pharmaceutically acceptable carrier and/or diluents are familiarto those skilled in the art. For compositions formulated as liquidsolutions, acceptable carriers and/or diluents include saline andsterile water, and may optionally include antioxidants, buffers,bacteriostats and other common additives. The compositions can also beformulated as pills, capsules, granules, or tablets which contain, inaddition to a CRF receptor antagonist, diluents, dispersing and surfaceactive agents, binders, and lubricants. One skilled in this art mayfurther formulate the CRF receptor antagonist in an appropriate manner,and in accordance with accepted practices, such as those disclosed inRemington's Pharmaceutical Sciences, Gennaro, Ed, Mack Publishing Co.,Easton, Pa. 1990.

[0108] In addition, prodrugs are also included within the context ofthis invention. Prodrugs are any covalently bonded carriers that releasea compound of structure (I) in vivo when such prodrug is administered toa patient. Prodrugs are generally prepared by modifying functionalgroups in a way such that the modification is cleaved, either by routinemanipulation or in vivo, yielding the parent compound.

[0109] With regard to stereoisomers, the compounds of structure (I) mayhave chiral centers and may occur as racemates, racemic mixtures and asindividual enantiomers or diastereomers. All such isomeric forms areincluded within the present invention, including mixtures thereof.Furthermore, some of the crystalline forms of the compounds of structure(I) may exist as polymorphs, which are included in the presentinvention. In addition, some of the compounds of structure (I) may alsoform solvates with water or other organic solvents. Such solvates aresimilarly included within the scope of this invention.

[0110] In another embodiment, the present invention provides a methodfor treating a variety of disorders or illnesses, including endocrine,psychiatric and neurologic disorders or illnesses. Such methods includeadministering of a compound of the present invention to a warm-bloodedanimal in an amount sufficient to treat the disorder or illness. Suchmethods include systemic administration of a CRF receptor antagonist ofthis invention, preferably in the form of a pharmaceutical composition.As used herein, systemic administration includes oral and parenteralmethods of administration. For oral administration, suitablepharmaceutical compositions of CRF receptor antagonists include powders,granules, pills, tablets, and capsules as well as liquids, syrups,suspensions, and emulsions. These compositions may also includeflavorants, preservatives, suspending, thickening and emulsifyingagents, and other pharmaceutically acceptable additives. For parentaladministration, the compounds of the present invention can be preparedin aqueous injection solutions which may contain, in addition to the CRFreceptor antagonist, buffers, antioxidants, bacteriostats, and otheradditives commonly employed in such solutions.

[0111] As mentioned above, administration of a compound of the presentinvention can be used to treat a wide variety of disorders or illnesses.In particular, the compounds of the present invention may beadministered to a warm-blooded animal for the treatment of depression,anxiety disorder, panic disorder, obsessive-compulsive disorder,abnormal aggression, unstable angina, reactive hypertension, anorexianervosa, bulimia, irritable bowel syndrome (IBS), inflammatory boweldisease (IBD), stress-induced immune suppression, stroke, inflammation,Cushing's disease, infantile spasms, epilepsy, and substance abuse orwithdrawal.

[0112] The following examples are provided for purposes of illustration,not limitation.

EXAMPLES

[0113] The CRF receptor antagonists of this invention may be prepared bythe methods disclosed in Examples 1 through 6. Example 7 presents amethod for determining the receptor binding activity (K_(i)), andExample 8 discloses an assay for screening compounds of this inventionfor CRF-stimulated adenylate cyclase activity.

[0114] In the Intermediates and Examples unless otherwise stated:

[0115] Melting points (m.p.) were determined on a Gallenkamp m.p.apparatus and are uncorrected. All temperatures are expressed as ° C.Infrared spectra were measured on a FT-IR instrument Proton MagneticResonance (¹H-NMR) spectra were recorded at 400 Mz, chemical shifts arereported in ppm downfield (d) from Me₄Si, used as internal standard, andare assigned as singlets (s), doublets (d), doublets of doublets (dd),triplets (t), quartets (q) or multiplets (m). Column chromatography wascarried out over silica gel (Merck AG Darmstaadt, Germany). Thefollowing abbreviations are used in text: EtOAc=ethyl acetate,cHex=cyclohexane, CH₂Cl₂=dichloromethane, Et₂O=dietyl ether,DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone;DMF=N,N-dimethylformamide, DIPEA=N,N-diisopropyl-ethylamine,MeOH=methanol, Et₃N=triethylamine, TBS=ter-butyldimethylsilyl;TBP=ter-butyldiphenylsilyl; TFA=trifluoroacetic acid,THF=tetrahydrofuran, DIBAL-H=diisobutylaluminium hydride,DMAP=dimethylaminopyridine, LHMDS=lithium hexamethyldisilazane; Tlcrefers to thin layer chromatography on silica plates, and dried refersto a solution dried over anhydrous sodium sulphate; r.t. (RT) refers toroom temperature.

Example 1 Synthesis of Representative Pyridine Intermediate

[0116]

[0117] Compound 2

[0118] Chloropyridine 1 is dissolved in THF and added to a stirredsuspension of LAH in THF at −78° C. The mixture is stirred for 6 hoursat this temperature and for 1 hour at −30° C. The mixture is thentreated cautiously with water, 15% aqueous NaOH and water with vigorousstiring. The mixture is warmed to room temperature and filtered. Thewhite precipitate is washed liberally with ethyl acetate. The combinedorganic portions are dried (MgSO₄) and concentrated under vacuum.Purification via flash chromatography gives the desired 2.

[0119] Compound 3

[0120] DMSO (6 equivalents) is added to a stirred solution of oxalylchloride (3 equivalents) in dichloromethane at −70° C. After 15 min,alcohol 2 (1 equivalent) in dichloromethane is added, followed bytriethylamine. The mixture is allowed to warm to room temperature andstirred for 1 hour. The mixture is washed with aqueous sodiumbicarbonate (75 mL), dried (MgSO₄), and concentrated under vacuum.Purification via flash chromatography gives the desired product 3.

[0121] Compound 4

[0122] Alkenylmagnesium bromide in THF (1 equivalent) is added to astirred solution of aldehyde 3 (1 equivalent) in THF at −78° C. Themixture is stirred at this temperature for 30 minutes, warmed to roomtemperature and quenched with aqueous sodium bicarbonate. The mixture isthen extracted with ethyl acetate and the combined extracts are dried(MgSO₄) and concentrated under vacuum. Purification via flashchromatography gives the desired 4.

Example 2 Synthesis of Representative Pyrimidine Intermediate

[0123]

[0124] Compound 2

[0125] The chloropyrimidine 1 is dissolved in THF and added to a stirredsuspension of LAH in THF at −78° C. The mixture is stirred or 6 hours atthis temperature and for 1 hour at −30° C. The mixture is then treatedcautiously with water, 15% aqueous NaOH and water with vigorousstirring. The mixture is warmed to room temperature and filtered. Thewhite precipitate is washed liberally with ethyl acetate. The combinedorganic portions are dried (MgSO₄) and concentrated under vacuum.Purification via flash chromatography gives the desired product 2.

[0126] Compound 3

[0127] DMSO (6 equivalents) is added to a stirred solution of oxalylchloride (3 equivalents) in dichloromethane at −70° C. After 15 min,alcohol 2 (1 equivalent) in dichloromethane is added, followed bytriethylamine. The mixture is allowed to warm to room temperature andstirred for 1 hour. The mixture is washed with aqueous sodiumbicarbonate (75 mL), dried (MgSO₄), and concentrated under vacuum.Purification via flash chromatography gives the desired product 3.

[0128] Compound 4

[0129] Alkenylmagnesium bromide in THF (1 equivalent) is added to astirred solution of aldehyde 3 (1 equivalent) in THF at −78° C. Themixture is stirred at this temperature for 30 minutes, warmed to roomtemperature and quenched with aqueous sodium bicarbonate. The mixture isextracted with ethyl acetate and the combined extracts are dried (MgSO₄)and concentrated under vacuum. Purification via flash chromatographygives the desired product 4.

Example 3 Synthesis of Representative Compounds of Structure (1)

[0130]

[0131] Compound 2:

[0132] The enone 1 (compound 4 from examples 1 and 2 above, 4.26 mmol),R₁NH₂ ( 4.3 mmol) and toluenesulfonic acid monohydrate (4.3 mmol) inethanol (20 mL) are heated at 60° C. for 16 hours. The mixture isconcentrated, taken up in ethyl acetate (50 mL), washed with aq. NaHCO₃(20 mL), dried (MgSO₄) and concentrated under vacuum. The residue ispurified on a silica gel column (elution with 25% ethyl acetate inhexanes) to afford 2.

[0133] Compound 4:

[0134] LDA in THF (0.325M, 0.83 mL, 0.27 mmol) is added to a stirredsolution of the phosphine oxide (66 mg, 0.27 mmol) in THF (2 mL) at −25°C. After 15 minutes, compound 2 (11 mg, 0.034 mmol) in THF (1 mL) isadded and the mixture is stirred for 15 min. NaH (30 mg) is added, themixture is warmed to room temperature and stirred for 16 hours. Themixture is diluted with water (15 mL) and extracted with EtOAc (4×10mL). The combined extracts are dried (MgSO4), concentrated in vacuo andthe residue is purified by preparative TLC (elution with 30% EtOAc/Hex.)to afford an oil which is then treated with TsOH.H₂O (4.2 mg, 0.022mmol) and R₄NH₂ (0.085 mmol) at 130° C. for 16 hours. The mixture iscooled to room temperature, diluted with aq. NaHCO₃ (2 mL) and extractedwith EtOAc (4×2 mL). The combined extracts are dried (MgSO₄),concentrated in vacuo and the residue is purified by preparative TLC toafford compound 4.

[0135] Compound 3:

[0136] Compound 2 (68 mg, 0.23 mmol) and R₄HNNH₂ (0.35 mmol) are heatedat 140° C. for 5 hours. The mixture is cooled to room temperature,diluted with aq. NaHCO₃ (2 mL) and extracted with EtOAc (4×2 mL). Thecombined extracts are dried (MgSO₄), concentrated in vacuo, and theresidue is purified by prep TLC (elution with 30% EtOAc/hexane) toafford compound 3.

Example 4 Synthesis of Representative Compounds of Structure (I)

[0137]

[0138] Compound 2

[0139] The enone 1 (compound 4 from examples 1 and 2, 4.26 mmol), R₁NH₂(4.3 mmol) and toluenesulfonic acid monohydrate (4.3 mmol) in ethanol(20 mL) are heated at 60° C. for 16 hours. The mixture is concentrated,taken up in ethyl acetate (50 mL), washed with aq. NaHCO₃ (20 mL), dried(MgSO₄) and concentrated under vacuum. The residue is purified on asilica gel column (elution with 25% ethyl acetate in hexanes) to afford2.

Compound 3:

[0140] Ketone 2 (0.16 mmol), p-toluenesulfonic acid monohydrate (30 mg,0.16 mmol) and R₄NH₂ (0.18 mmol) are dissolved in ethanol (0.5 mL) andheated at 80° C. in a sealed tube for 20 hours. The mixture is cooled toroom temperature, diluted with aq. NaHCO₃ (2 mL), and extracted withethyl acetate (4×2 mL). The combined organic extracts are dried (MgSO₄),concentrated under vacuum, and the residue is purified by preparativeTLC to afford 3.

[0141] Compound 4a: (Z=O, Y═O)

[0142] Ketone 3 (0.095 mmol) is dissolved in methanol (1 mL) and treatedwith sodium borohydride (25 mg, 0.66 mmol). The mixture is stirred for 4hours, diluted with aq. NaHCO₃ (2 mL), and extracted with ethyl acetate(4×2 mL). The combined organic extracts are dried (MgSO₄), concentratedunder vacuum, and the residue is taken up in toluene (1 mL) and treatedwith a solution of phosgene in toluene (20%, 0.1 mL). After 16 hours,the solution is concentrated under vacuum and the residue is purified bypreparative TLC to afford 32 mg (75%) of carbonate 4a as a yellow oil.

[0143] Compound 4b: (Z=S, Y═O)

[0144] Ketone 3 (0.095 mmol) is dissolved in methanol (1 mL) and treatedwith sodium borohydride (25 mg, 0.66 mmol). The mixture is stirred for 4hours, diluted with aq. NaHCO₃ (2 mL), and extracted with ethyl acetate(4×2 mL). The combined organic extracts are dried (MgSO₄), concentratedunder vacuum, and the residue is taken up in toluene (1 mL) and treatedwith a solution of thiophosgene in toluene (20%, 0.1 mL). After 16hours, the solution is concentrated under vacuum and the residue ispurified by preparative TLC to afford 25 mg (55%) of 7b as a yellow oil.

[0145] Compound 4c: (Z=O, Y═NR₇)

[0146] Ketone 3 (0.095 mmol) and amine (0.20 mL) are dissolved inacetonitrile (1 mL) and are treated with sodium cyanoborohydride (25mg). Acetic acid (1 drop) is added and the mixture is stirred for 4hours, diluted with aq. NaHCO₃ (2 mL), and extracted with ethyl acetate(4×2 mL). The combined organic extracts are dried (MgSO₄), concentratedunder vacuum, and the residue is taken up in toluene (1 mL) and treatedwith a solution of phosgene in toluene (20%, 0.1 mL). After 18 hours,the solution is concentrated under vacuum and the residue is purified bypreparative TLC to afford urea 4c.

[0147] Compound 4d: (Z=S, Y═NR₇)

[0148] Ketone 3 (0.095 mmol) and amine (0.20 mL) are dissolved inacetonitrile (1 mL) and are treated with sodium cyanoborohydride (25mg). Acetic acid (1 drop) is added and the mixture is stirred for 4hours, diluted with aq. NaHCO₃ (2 mL), and extracted with ethyl acetate(4×2 mL). The combined organic extracts are dried (MgSO₄), concentratedunder vacuum, and the residue is taken up in toluene (1 mL) and treatedwith a solution of thiophosgene in toluene (20%, 0.1 mL). After 18hours, the solution is concentrated under vacuum and the residue ispurified by preparative TLC to afford thiourea 4d

[0149] Compound 5a: (Z=O)

[0150] Ketone 3 (0.16 mmol), urea (30 mg) and ZnCl₂ (25 mg) are heatedat 200° C. for 5 h. The mixture is cooled to room temperature, dilutedwith aq. NaHCO₃ (2 mL), and extracted with ethyl acetate (4×2 mL). Thecombined organic extracts are dried (MgSO₄), concentrated under vacuum,and the residue is purified by preparative TLC to afford urea 5a.

[0151] Compound 5b: (Z=NR₉)

[0152] The urea from the above procedure (5a, 0.070 mmol) and PCl₅ (15mg, 0.070 mmol) are heated in toluene at 90° C. for 3 hours during whichtime a white solid forms. The mixture is cooled to room temperature andis treated with amine (0.10 mL). Stirring is continued for 30 minutes.The mixture is diluted with aq. NaHCO₃ (2 mL), and extracted with ethylacetate (4×2 mL). The combined organic extracts are dried (MgSO₄),concentrated under vacuum, and the residue is purified by preparativeTLC to afford guanidine 5b.

[0153] Compound 5c: (Z=S)

[0154] The urea from the above procedure (5a, 0.070 mmol) and P₄S₁₀ (50mg) are heated in toluene at 90° C. for 20 hours. The mixture is cooledto room temperature, diluted with aq. NaHCO₃ (2 mL), and extracted withethyl acetate (4×2 mL). The combined organic extracts are dried (MgSO₄),concentrated under vacuum, and the residue is purified by preparativeTLC to afford thiourea 5c.

Example 5 Synthesis of Representative Compounds of Structure (XIa)

[0155]

[0156] Intermediate 1

(4,6-Dichloro-2-methyl-pyrimidin-5-yl)-acetic acid methyl ester

[0157] Sodium (1.74 g, 3 eq) was added portionwise to anh. MeOH (60 mL),at 0° C., under N₂. After consumption of metallic sodium, acetamidinehydrochloride (7.06 g, 3 eq) was added. After 20 min. of stirring, theprecipitated NaCl was filtered off. A solution of2-ethoxycarbonyl-succinic acid diethyl ester (6.04 g, 24.5 mmol) inanhydrous MeOH (20 mL) was added to the solution of free acetamidine andthe mixture was stirred at r.t. for 2 days. The reaction mixture wasconcentrated to dryness in vacuo and the yellow foam (8.69 g) obtainedwas then mixed with POCl₃ (70 mL) and heated at reflux for 3.5 hr. Theresulting solution was cooled to room temperature and poured slowly intoice/water (600 mL) and NH₄OH (50 mL) with vigorous stirring. The productwas extracted with EtOAc (3×50 mL) and with Et₂O (3×20 mL). The combinedorganic extracts were washed with H₂O (60 mL) and brine (40 mL), driedover Na₂SO₄, filtered and concentrated in vacuo. The crude oil waspurified by flash chromatography (silica gel, cHex/AcOEt 9:1).Intermediate 1 was obtained as a yellow solid (4.27 g, 73%)

[0158] NMR (¹H, CDCl₃): δ 5.85 (m, 1H), 5.15 (dq, 1H), 5.11 (dq, 1H),3.61 (dt, 2H), 2.67 (s, 3H). MS (m/z): 202 [M]⁺.2Cl; 167 [MH—Cl]⁺,1Cl.

[0159] Intermediate 2

2-(4,6-Dichloro-2-methyl-pyrimidin-5yl)-pent-4-enoic acid methyl ester

[0160] To a solution of intermediate 1 (3 g, 1 eq) in anh. THF (60 mL),at −78° C., under N₂, LiHMDS (1M in THF) (16.03 mL, 1.25 eq) was addeddropwise. The reaction mixture was cooled at 0° C. and stirred for 30min. The reaction mixture was cooled at −78° C. and allyl iodide (1.58mL, 1.35 eq) was added dropwise in 1.5 h. The reaction mixture wasstirred at r.t. for 3 h. Then water (30 mL) was added and reactionmixture was extracted with EtOAc (3×60 mL). The organic layers weregathered and washed with sat.aq. NaCl (1×20 mL) and dried over anh.Na₂SO₄. The solids were filtered and the solvent evaporated to give acrude product, which was purified by flash chromatography (silica gel,5% EtOAc/Cyclohexane). Intermediate 2 was obtained as a white solid (2.4g, 8.76 mmol, 68%)

[0161] NMR (¹H, CDCl₃): δ 5.77 (m, 1H), 5.03 (m, 2H), 4.43 (dd, 1H),3.76 (s, 3H), 3.12 (m, 1H), 2.78 (m, 1H), 2.73 (s, 3H). MS (m/z): 275[MH]⁺

[0162] Intermediate 3

2-(4,6-Dichloro-2-methyl-pyrimidin-5-yl)-pent-4en-1-ol

[0163] To a solution of intermediate 2 (257 mg, 0.937 mmol) in anh.CH₂Cl₂ (9.3 ml), at −78° C., under N₂, was added DIBAl—H (1M solution inhexane, 5.6 mL, 6 eq). After the DIBAl—H addition the reaction mixturewas stirred at −78° C. for 1 hr and 2 hr at 0° C. The reaction mixturewas poured into a solution of HCl 0.5N in ice (20 ml) and extracted withCH₂Cl₂ (3×10 mL). The combined organic extracts were dried over Na₂SO₄,filtered and concentrated in vacuo. 200 mg of intermediate 3 wasobtained as a colourless oil (yield 86%).

[0164] NMR (¹H, CDCl₃): δ 5.76 (m, 1H), 5.12 (m, 1H), 5.01 (m, 1H), 4.16(m, 1H), 4.06 (m, 1H), 3.91 (m, 1H), 2.8-2.6 (m, 2H), 2.70 (s, 3H), 1.50(t, 1H). MS (m/z): 247 [M]⁺, 2Cl

[0165] Intermediate 4

5-[1-(tert-Butyl-diphenyl-silanyloxymethyl)-but-3-enyl]4,6-dichloro-2-methyl-pyrimidine

[0166] To a solution of intermediate 3 (152 mg, 0.61 mmol) in anh. DMF(4 ml), at 0° C., under N₂, was added 4-DMAP (3.8 mg, 0.05 eq),imidazole (420 mg, 10 eq) and Ph₂tBuSiCl (0.32 mL, 2 eq). The reactionmixture was stirred at r.t. for 2 hr. To this solution were added 5 mlof sat.aq. NH₄Cl in water and the mixture was extracted with Et₂O (2×15ml). The combined organic extracts were washed once with water, oncewith brine and dried over Na₂SO₄. The solids were filtered, the solventwas evaporated and the crude yellow oil was purified by flashchromatography (silica gel, cHex/EtOAc 95:5). Intermediate 4 wasobtained as a colourless oil (270 mg, 0.55 mmol, 90%).

[0167] NMR (¹H, CDCl₃): δ 7.65 (dd, 2H), 7.56 (dd, 2H), 7.49-7.36 (m,6H), 5.67 (m, 1H), 5.03 (dd, 1H), 4.94 (dd, 1H), 4.17 (m, 1H), 4.00 (m,2H), 2.70 (s, 3H), 2.69 (m, 1H), 2.55 (m, 1H), 0.98 (s, 9H). MS (m/z):485 [MH]⁺, 2Cl.

[0168] Intermediate 5

4-(tert-Butyl-diphenyl-silanyloxy)-3-(4,6-dichloro-2-methyl-pyrimidin-5yl)-1-ol

[0169] To a solution of intermediate 4 (1.52 g, 3.14 mmol) in anh.CH₂Cl₂/MeOH mixture (4/1 v/v, 50 mL), at −78° C., O₃ was bubbled for 15min while stirring. The reaction mixture was diluted with anh. MeOH (10mL) and NaBH₄ (475 mg, 4 eq) was added, at −78° C. The reaction mixturewas stirred at r.t. for 3 hr, then quenched with sat.aq. NH₄Cl (15 mL)and the product was extracted with EtOAc (3×60 mL). The combined organiclayers were washed with sat.aq. NaCl (1×20 mL) and dried over anh.Na₂SO₄. The solids were filtered and the solvent evaporated to give acrude product, which was purified by flash chromatography (silica gel,cHex/EtOAc 8:2). Intermediate 5 was obtained as a yellow oil (1.14 g,2.34 mmol, 74%).

[0170] NMR (¹H, DMSO): δ 7.55-7.33 (, 10H), 4.46 (t, 1H), 4.09,397,2.92(m, 3H), 3.40-3.20 (m, 2H), 2.00-1.76 (m, 2H), 2.56 (s, 3H), 0.84 (s,9H). MS (m/z): 489 [MH]⁺.

[0171] Intermediate 6

Methanesulfonic acid4-(tert-butyl-diphenyl-silanyloxy)-3-(4,6-dichloro-2-methyl-pyrimidin-5-yl)-butylester

[0172] To a solution of intermediate 5 (1.14 g, 2.33 mmol) in anh.CH₂Cl₂ (46 mL), at 0° C., Et₃N (1.6 mL, 5 eq) and MsCl (378 μL, 2.1 eq)were added. The reaction mixture was stirred at r.t. for 30 min. Thenwater (15 mL) was added and reaction mixture was extracted with CH₂Cl₂(3×60 mL). The combined organic layers were washed with sat.aq. NaCl(1×20 mL) and dried over anh. Na₂SO₄. The solids were filtered and thesolvent evaporated to give a crude product, which was purified by flashchromatography (silica gel, cHex/EtOAc 8:2). Intermediate 6 was obtainedas a yellow oil (1.28 g, 2.26 mmol, 97%).

[0173] NMR (¹H, DMSO): δ 7.60-7.30 (m, 10H), 4.20,4.10-3.90 (m,m, 5H),3.07 (s, 3H), 2.57 (s, 3H), 2.34-2.06 (m, 2H), 0.84 (s, 9H). MS (m/z):567 [MH]⁺.

[0174] Intermediate 7

5-(tert-Butyl-diphenyl-silanyloxymethyl)-4-chloro-2-methyl-8-[4-(1,1,2-trifluoro-ethyl)-2-trifluoromethyl-phenyl]-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidine

[0175] To a solution of 2,4-bis(trifluoromethyl)aniline (15.6 mg, 1 eq)in anh. DMF (1 mL), at 0° C., NaH 80%/oil (4.5 mg, 2.2 eq) was added.The reaction mixture was stirred at 0° C. for 15 min then at r.t. for 15min. The reaction mixture was cooled at 0° C. and a solution ofintermediate 6 (38.7 mg, 0.068 mmol) in anh. DMF (0.3 mL) was added. Thereaction mixture was stirred at r.t. for 1.5 hr. Then water (2 mL) wasadded and the reaction mixture was extracted with EtOAc (3×7 mL). Thecombined organic layers were washed with sat.aq. NaCl (1×10 mL) anddried over anh. Na₂SO₄. The solids were filtered and the solventevaporated to give a crude product, which was purified by flashchromatography (silica gel, cHex/EtOAc 9:1). Intermediate 7 was obtainedas a yellow oil (19.4 mg, 0.029 mmol, 43%).

[0176] NMR (¹H, CDCl₃): δ 7.98,7.94 (d,d, 1H), 7.88,7.80 (dd,dd, 1H),7.77-7.58, 7.44-7.32 (m,m, 1H), 3H), 7.35,7.14 (d,d, 1H), 3.98,3.94 (dd,dd, 1H), 3.73,3.55 (t,m, 1H), 3.63,3.59 (m,m, 1H), 3.44-3.36 (m, 2H),3.38-3.30 (m, 2H), 2.55,2.40 (m,m, 1H), 2.17,2.15 (s,s 1H), 2.04,1.90(m,m, 1H), 0.98 (s, 9H). MS (m/z): 664 [MH]⁺.

Intermediate 8{4-Chloro-2-methyl-8-[4-(1,1,2-trifluoro-ethyl)-2-trifluoromethyl-phenyl]-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-5-yl}-methanol

[0177] To a solution of intermediate 7 (52 mg, 0.078 mmol) in anh. DMF(1 mL), at r.t., under N₂, Et₃N.3HF (102 μL, 8 eq.) was added and thereaction mixture was stirred at r.t. overnight. It was then diluted withwater (2 mL) and extracted with Et₂O (3×5 mL). The combined organiclayers were washed with sat.aq. NaCl (1×7 mL) and dried over anh.Na₂SO₄. The solids were filtered and the solvent evaporated: The crudeproduct was purified by flash chromatography (silica gel, cHex/EtOAc6:4). Intermediate 8 was obtained as a clear oil (27 mg, 0.063 mmol,81%). NMR (¹H, DMSO): δ 8.26-8.12 (m, 2H), 7.90-7.80 (d, 1H), 5.08-4.98(t, 1H), 3.90-3.60 (2H), 3.70-3.30 (2H), 3.24-3.10 (1H), 2.30 (m, 1H),2.09 (s, 3H), 2.00-1.80 (m, 1H). MS (m/z): 425 [MH]⁺.

[0178] Intermediate 9

Methanesulfonic acid4-chloro-2-methyl-8-[4-(1,1,2-trifluoro-ethyl)-2-trifluoromethyl-phenyl]-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-5-yl-methylester

[0179] To a solution of intermediate 8 (130 mg, 0.306 mmol) in anh.CH₂Cl₂ (4 mL), at 0° C., Et₃N (213 μL, 5 eq) and MsCl (50 μL, 2.1 eq)were added. The reaction mixture was stirred at r.t. for 3 hr. Thenwater (8 mL) was added and the reaction mixture was extracted withCH₂Cl₂ (3×20 mL). The combined organic layers were washed with sataq.NaCl (1×10 mL) and dried over anh. Na₂SO₄. The solids were filtered andthe solvent evaporated to give a crude product, which was purified byflash chromatography (silica gel, cHex/EtOAc 65/35). Intermediate 9 wasobtained as a clear oil (138 mg, 0.274 mmol, 90%).

[0180] NMR (¹H, DMSO): δ 8.30-8.14 (m, 2H), 7.95-7.80 (d,d, 1H),4.56-4.20 (2H), 3.9-3.94 (m, 3H), 3.25 (s, 3H), 2.11 (s, 3H), 2.2-1.9(m, 2H). MS (m/z): 425 [MH]⁺.

[0181] Intermediate 10

7-Methyl-1-(1-propyl-butyl)-5-[4-(1,1,2-trifuoro-ethyl)-2-trifluoromethyl-phenyl]-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraaza-acenaphthylene

[0182] A mixture of intermediate 9 (135 mg, 0.27 mmol) and heptyl amine(0.5 mL, 12 eq.) was heated at 130° C. (screw cap vial, sand bath) for 3hr. The reaction mixture was then cooled down to r.t. and diluted withCH₂Cl₂ (3 mL). The solvent was evaporated and the crude product waspurified by flash chromatography (silica gel, cHex/EtOAc 9:1).Intermediate 10 was obtained as a yellow solid (29.4 mg, 0.06 mmol,23%).

[0183] NMR (¹H, CDCl₃): δ 7.99 (s, 1H), 7.83 (d, 1H), 7.48 (d, 1H),4.06-3.24 (bm, 5H), 2.23-2.2 (bm, 4H), 1.74-1.1 (bm, 10H), 0.97 (t, 3H),0.91 (t, 3H). MS (m/z): 487 [MH]⁺.

Intermediate 114-[5-(tert-Butyl-diphenyl-silanyloxymethyl)-4-chloro-2-methyl-6,7-dihydro-5H-pyrido[2,3-d]pyrimidin-8-yl]-3-methyl-benzonitrile

[0184] To a solution of 4-amino-3-methylbenzonitrile (14 mg, 0.106 mmol)in DMF (3.5 mL), at 0° C., under N₂, NaH 80%/oil (4.5 mg, 0.112 mmol)was added. Intermediate 6 (60 mg, 0.106 mmol) was added after 30 min,and the reaction mixture was stirred at r.t. for 2 hr. It was thencooled down to r.t. and diluted with water (20 mL). The product wasextracted with EtOAc (3×25 mL). The combined organic extracts werewashed with sat.aq. NaCl (2×20 mL), and dried over anh. Na₂SO₄. Thesolids were filtered and the solvent evaporated. The crude product waspurified by flash chromatography (silica gel, cyclohexane/EtOAc 80%).Intermediate 11 was obtained as a clear oil (28 mg, 0.52 mmol, y=47%).

[0185] NMR (¹H, CDCl₃): δ 7.65 (s, 1H), 7.55 (m, 4H), 7.35 (m, 6H), 7.10(d, 1H), 6.95 (d, 1H), 3.92 (m, 1H), 3.8 (m, 2H), 3.5-3.3 (m, 2H), 2.21(m, 1H), 2.44 (s, 3H), 2.10 (s, 3H), 1.61 (m, 1H), 1.10 (s, 9H). MS(m/z): 567[MH]⁺.

[0186] Intermediate 12

4-(4-Chloro-5-hydroxymethyl-2-methyl-6,7dihydro-5H-pyrido[2,3d]pyrimidin-8-yl)-3-methyl-benzonitrile

[0187] To a solution of intermediate 11 (28 mg, 0.05 mmol) in anh. DMF(2.5 mL), at r.t., under N₂, Et₃N.3HF (44 μL, 0.290 mmol) was added andthe reaction mixture was stirred at r.t. for 12 hr. It was diluted withwater (20 mL), and the product was extracted with EtOAc (3×25 mL). Thecombined organic layers were washed with sat. aq. NaCl (2×20 mL) anddried over anh. Na₂SO₄. The solids were filtered and the solventevaporated. The crude product was purified by flash chromatography(silica gel, cHex/EtOAc 6:4). Intermediate 11 was obtained as a clearoil (22 mg, 0.08 mmol, 75%). NMR (¹H, CDCl₃): δ 7.61-7.58 (m, 2H), 7.27(m, 1H), 3.92-3.81 (m, 3H), 3.50-3.35 (m, 2H), 2.4 (m, 1H), 2.26 (s,3H), 2.19 (s, 3H), 1.8 (m, 1H). MS (m/z): 329[MH]⁺.

[0188] Intermediate 13

4-[1-(1-Ethyl-propyl)-7-methyl-2,2a,3,4-tetrahydro-1H-1,5,6,8-tetraaza-acenaphthylen-5-yl]-3-methyl-benzonitrile

[0189] To a solution of intermediate 12 (43 mg, 0.131 mmol) in anh.CH₂Cl₂ (2.5 mL), at 0° C., under N₂, MsCl (13 μL, 0.328 mmol) and Et₃N(87 μL 0.655 mmol) were added the reaction mixture was stirred at r.t.for 1 hr, and then diluted with water (20 mL). The reaction mixture wasextracted with EtOAc. (3×25 mL). The combined organic layers were washedwith sat. aq. NaCl (2×20 mL)and dried over anh. Na₂SO₄. The solids werefiltered and the solvent evaporated. The crude product was dissolved in3-amino-pentane (143 μL, 1.23 mmol.) and the reaction mixture was heatedat 100° C. (screw cap vial, sand bath) for 16 hr. It was then cooleddown to r.t. and the reaction mixture was purified by flashchromatography (silica gel, cHex/EtOAc 75:25). Intermediate 13 wasobtained as a white solid (23 mg, 0.074 mmol, 50%).

[0190] NMR (¹H, CDCl₃): δ 7.50 (d, 1H), 7.30 (dd, 1H), 7.55 (d, 1H) 3.86(m, 1H), 3.70-3.23 (t+t, 2H), 3.43 (m, 1H), 3.63 (m, 2H), 2.27 (s, 3H),2.24 (s, 3H), 2.18 (r, 1H), 1.74 (m, 1H), 1.59-1.45 (m, 4H), 0.99-0.78(t+t 6H). MS (m/z): 362[MH]⁺.

[0191] Intermediate 14

3-Methyl-4-[7-methyl-1-(1-propyl-butyl)-2,2a,3,4-tetrahydro-1H-1,5,6,8tetraaza-ace-naphthylen-5-yl]-benzonitrile

[0192] To a solution of intermediate 12 (14 mg, 0.043 mmol) in anh.CH₂Cl₂ (1.5 mL), at 0° C., under N₂, MsCl (4μL, 0.109 mmol) and Et₃N (28μL 0.216 mmol) were added the reaction mixture was stirred at r.t. for 1hr, and then diluted with water (20 mL). The product was extracted withEtOAc (3×25 mL). The combined organic layers were washed with sat. aq.NaCl (2×20 mL) and dried over anh. Na₂SO₄. The solids were filtered andthe solvent evaporated. The crude product was dissolved in 4-heptylamine(50 μL, 0.349 mmol) and the reaction mixture was heated at 100° C.(screw cap vial, sand bath) for 16 hr. It was then cooled down to r.t.and the reaction mixture was purified by flash chromatography (sililcagel, cHex/EtOAc 75:25). Intermediate 14 was obtained as a white solid(5.0 mg, 0.020 mmol, 40%).

[0193] NMR (¹H, CDCl₃): δ 7.73 (s, 1H), 7.65 (dd, 1H), 7.41 (d, 1H) 3.95(m, 1H), 3.78-3.6 (m, 2H), 3.5-3.24 (t, 2H), 2.27 (m, 1H), 2.18 (s, 3H),2.10 (s, 3H), 1.65 (m, 1H), 1.55-1.40 (m, 4H), 1.38-1.10 (m, 4H),0.95-0.88 (t+t, 6H). MS (m/z): 389[MH]⁺.

Intermediate 154-[5-(tert-Butyl-diphenyl-silanyloxymethyl)-4-chloro-2-methyl-6,7-dihydro-5H-pyrido[2,3-d]pyrimidin-8-yl]-3-chloro-benzonitrile

[0194] To a solution of 4-amino-3-chlorobenzonitrile (86 mg, 0.566 mmol)in DMF (3.5 mL), at 0° C., under N₂, NaH 80%/oil (17 mg, 0.566 mmol) wasadded. Intermediate 6 (308 mg, 0.546 mmol) was added after 30 min, andthe reaction mixture was stirred at r.t. for 2 hr. It was then cooleddown to r.t. and diluted with water (30 mL). The product was extractedwith EtOAc (3×45 mL). The combined organic extracts were washed withsat.aq. NaCl (2×20 μL), and dried over anh. Na₂SO₄. The solids werefiltered and the solvent evaporated. The crude product was purified byflash chromatography (silica gel, cHex/EtOAc 8:2). Intermediate 15 wasobtained as a clear oil (110 mg, 0.184 mmol, 35%).

[0195] NMR (¹H, CDCl₃): δ 7.65 (s, 1H), 7.55 (m, 4H), 7.35 (m, 6H),7.10(d, 1H), 6.95 (d, 1H), 3.92 (m, 1H), 3.8 (m, 2H), 3.5-3.3 (m, 2H),2.21 (m, 1H), 2.10 (s, 3H), 1.61 (m, 1H), 1.10 (s, 9H). MS (m/z):587[MH]⁺.

[0196] Intermediate 16

3-Chloro-4-(4-chloro-5-hydroxymethyl-2-methyl-6,7-dihydro-5H-pyrido[2,3-d]pyrimidin-8-yl)benzonitrile

[0197] To a solution of intermediate 15 (110 mg, 0.19 mmol) in anh. DMF(2.5 mL), at r.t., under N₂, Et₃N.3HF (260 μL, 1.91 mmol) was added andthe reaction mixture was stirred at r.t. for 12 hr. It was diluted withwater (20 mL), and the product was extracted with EtOAc (3×20 mL). Thecombined organic layers were washed with sat aq. NaCl (2×20 mL) anddried over anh. Na₂SO₄. The solids were filtered and the solventevaporated. The crude product was purified by flash chromatography(silica gel, cHex/EtOAc 6:4). Intermediate 16 was obtained as clear oil(53 mg, 0.15 mmol, 81%).

[0198] NMR (¹H, CDCl₃): δ 7.95-8.8(m, 2H), 7.3(d, 1H), 3.9(m, 1H), 3.(m,2H), 3.5-3.3 (m, 2H), 2.2 (m, 1H), 2.15 (s, 3H), 1.8 (m, 1H). MS (m/z):349[MH]⁺.

[0199] Intermediate 17

3-Chloro-4-[7-methyl-1-(1-propyl-butyl)-2,2a,3,4-tetrahydro-1H-1,5,6,8-tetraaza-acenaphthylen-5-yl]-benzonitrile

[0200] To a solution of intermediate 16 (52 mg, 0.149 mmol) in anh.CH₂Cl₂ (1.5 mL), at 0° C., under N₂, MsCl (16 μL, 0.373 mmol) and Et₃N(90 μL 0.745 mmol) were added. The reaction mixture was stirred at r.t.for 1 hr, and then diluted with water (20 mL). The product was extractedwith EtOAc (3×25 mL). The combined organic layers were washed with sat.aq. NaCl (2×20 mL) and dried over anh. Na₂SO₄. The solids were filteredand the solvent evaporated. The crude product was dissolved in4-heptylamine (188 μL, 1.49 mmol.) and the reaction mixture was heatedat 100° C. (screw cap vial, sand bath) for 16 hr. It was then cooleddown to r.t. and the reaction mixture was purified by flashchromatography (slilca gel, cHex/EtOAc 8:2). Intermediate 17 wasobtained as a white solid (36.0 mg, 0.084 mmol, 60%).

[0201] NMR (¹H, CDCl₃): δ 7.74 (d, 1H), 7.56 (dd, 1H), 7.49 (d, 1H) 4.05(m, 1H), 3.78-3.6 (m, 2H), 3.5-3.24 (t, 2H), 2.27 (s, 3H), 2.18 (m, 1H),1.55-1.40 (m, 4H), 1.38-1.10 (m, 4H), 0.95-0.88 (t+t 6H). MS (m/z):410[MH]⁺.

[0202] Intermediate 18

3-Chloro-4-[1-(1-ethyl-propyl)-7-methyl-2,2a,3,4-tetrahydro-1H-1,5,6,8-tetraaza-acenaphthylen-5-yl]-benzonitrile

[0203] To a solution of intermediate 16 (35 mg, 0.112 mmol) in anh.CH2Cl₂ (1.5 mL), at 0° C., under N₂, MsCl (12 μl, 0.277 mmol) and Et₃N(68 μl 0.560 mmol) were added and the reaction mixture was stirred atr.t. for 1 hr, and then diluted with water (20 mL). The product wasextracted with EtOAc (3×25 mL). The combined organic layers were washedwith sat. aq. NaCl (2×20 mL) and dried over anh. Na₂SO₄. The solids werefiltered and the solvent evaporated. The crude product was dissolved in3-amino-pentane (158 μL, 1.12 mmol.) and the reaction mixture was heatedat 100° C. (screw cap vial, sand bath) for 16 hr. It was then cooleddown to r.t. and the reaction mixture was purified by flashchromatography (slilca gel, cHex/EtOAc 75:25). Intermediate 18 wasobtained as a white solid (18.0 mg, 0.084 mmol, 53%).

[0204] NMR (¹H, CDCl₃): δ 7.74 (d, 1H), 7.55 (dd, 1H), 7.50 (d, 1H) 3.95(mn, 1H), 3.78-3.65 (m, 2H), 3.45 (m, 1H), 3.69-3.23 (t+t, 2H), 2.28 (s,3H), 2.18 (m, 1H), 1.55-1.46 (m, 4H), 0.97-0.78 (t+t, 6H). MS (m/z):382[MH]⁺.

[0205] Intermediate 19

5-(2,4-Bis-trifluoromethyl-phenyl)-1-(1-ethyl-propyl)-7-methyl-1,2,2a,3,4,5-hexahydro-1,5,6,8-tetraaza-acenaphthylene

[0206] To a solution of intermediate 8 (45 mg, 0.106 mmol) in anh.CH₂Cl₂ (2.5 mL), at 0° C., under N₂, MsCl (10 μL, 0.265 mmol) and Et₃N(70 μL 0.530 mmol) were added and the reaction mixture was stirred atr.t. for 1 hr, and then diluted with water (20 mL). The product wasextracted with EtOAc (3×25 mL). The combined organic layers were washedwith sat. aq. NaCl (2×20 mL) and dried over anh Na₂SO₄. The solids werefiltered and the solvent evaporated The crude product was dissolved in3-amino-pentane (184 μL, 0.992 mmol.) and the reaction mixture washeated at 100° C. (screw cap vial, sand bath) for 16 hr. It was thencooled down to r.t. and the reaction mixture was purified by flashchromatography (silica gel, cHex/EtOAc 75:25). Intermediate was obtainedas a white solid (28.0 mg, 0.064 mmol, 60%).

[0207] NMR (¹H, CDCl₃): δ 7.98 (d, 1H), 7.83 (dd, 1H), 7.49 (d, 1H) 3.87(m, 1H), 3.70-3.23 (t+t, 2H), 3.44 (m, 1H), 3.63 (m, 2H), 2.23 (s, 3H),2.18 (m, 1H), 1.55-1.47 (m, 4H), 0.99-0.88 (t+t, 6H). MS (m/z):458[MH]⁺.

Example 5-1-17-Methyl-1-(1-propyl-butyl)-5-[4-(1,1,2-trifluoro-ethyl-2-trifluoromethylphenyl]-1,2,2a,3,4,5-exahydro-1,5,6,8tetraaza-acenaphtylene

[0208] To a solution of intermediate 10 (21 mg, 0.043 mmol) in anh.CH₂Cl₂ (1.0 mL), DDQ (9.7 mg 1 eq) was added. The reaction mixture wasstirred at r.t. for 3.5br. The solvent was evaporated and the crudeproduct was purified by flash chromatography (silica gel, cHex/EtOAc9:1). Example 5-1-1 was obtained as a clear oil (14 mg, 0.028 mmol,67%).

Example 5-1-23-Methyl-4-[7-methyl-1-(1-propyl-butyl-3,4-dihydro-1,H-1,5,6,8-tetraaza-acenaphthylen-5-yl]-benzonitrile

[0209] To a solution of intermediate 14 (15 mg, 0.038 mmol) in CH₂Cl₂(1.5 mL), DDQ (9.6 mg 0.042 mmol) was added. The reaction mixture wasstirred at r.t. for 3 hr. The solvent was evaporated and the crudeproduct was purified by flash chromatography (silica gel,cyclohexane/EtOAc 7:3) Example 5-1-2 was obtained as a white solid (8mg, 0.021 mmol, 56%).

Example 5-1-34-[1-(1-Ethyl-propyl)-7-methyl-3,4dihydro-1H-1,5,6,8-tetraaza-acenaphthylen-5-yl]-3-methyl-benzonitrile

[0210] To a solution of intermediate 13 (18 mg, 0.049 mmol) in CH₂Cl₂(1.5 mL), DDQ (14.5 mg 0.064 mmol) was added. The reaction mixture wasstirred at r.t. for 3 hr. The solvent was evaporated and the crudeproduct was purified by flash chromatography (slilca gel, cHex/EtOAc7:3). Example 5-1-3 was obtained as a white solid (10 mg, 0.029 mmol,60%).

Example 5-1-43-Chloro-4-[7-methyl-1-(1-propyl-butyl)-3,4-dihydro-1H-1,5,6,8-tetraaza-acenaphthylen-5-yl]-benzonitrile

[0211] To a solution of intermediate 17 (15 mg, 0.04 mmol) in anh.CH₂Cl₂ (1.0 mL), DDQ (14.5 mg 0.064 mmol) was added. The reactionmixture was stirred at r.t. for 3 hr. The solvent was evaporated and thecrude product was purified by flash chromatography (silica gel,cHex/EtOAc 7:3). Example 5-1-4 was obtained as a white solid (8.1 mg,0.02 mmol, 56%).

Example 5-1-53-Chloro-4-[1-(1-ethyl-propyl)-7-methyl-3,4-dihydro-1H-1,5,6,8-tetraaza-acenaphthylen-5-yl]-benzonitrile

[0212] To a solution of intermediate 18 (12 mg, 0.032 mmol) in anh.CH₂Cl₂(1.0 mL), DDQ (10.5 mg 0.042 mmol) was added. The reaction mixturewas stirred at r.t. for 3 hr. The solvent was evaporated and the crudeproduct was purified by flash chromatography (slilca gel, cHex/EtOAc7:3). Example 5-1-5 was obtained as a white solid (8.0 mg, 0.02 mmol,60%).

Example 5-1-65-(2,4-Bis-trifluoromethyl-phenyl-1-(1-ethyl-propyl)-7-methyl-1,3,4,5-tetrahydro-1,5,6,8-tetraaza-acenaphthylene

[0213] To a solution of intermediate 19 (20 mg, 0.044 mmol) in anh.CH₂Cl₂ (1.5 mL), DDQ (12.5 mg 0.053 mmol) was added. The reactionmixture was stirred at r.t. for 3 h The solvent was evaporated and thecrude product was purified by flash chromatography (slilca gel,cHex/EtOAc 7:3). Example 5-1-6 was obtained as a white solid (11 mg,0.024 mmol, 60%).

[0214] All the analytical data are set forth in the following Table 1.TABLE 1 (XIa)

Cpd. R₈, R₅, No. R₁ R₂ R_(4″) R_(6″) Analitycal Data 5-1-12,4-bistrifluoro- methylphenyl CH₃

H NMR(¹H, CDCl₃): δ 8.05(s, 1H), 7.89(d, 1H), 7.65(d, 1H), 6.58(s, 1H),4.62(m, 1H), 3.78(m, 2H), 3.40-3.00(m, 2H), 2.49(s, 3H), 1.80(m, 8H),1.30-1.10, 0.88 (m, t, 8H). MS(m/z): 485[MH]⁺. 5-1-2 2-methyl-4-cyanophenyl CH₃

H NMR(¹H, CDCl₃): δ 7.59(d, 1H), 7.56(d, 1H), 7.40(dd, 1H), 6.59 (s,1H), 4.65(m, 1H), 3.84(t, 2H), 3.14(t, 2H), 2.52(s, 3H), 2.28(s, 3H),1.79(m, 4H), 1.25(m, 4H), 0.84(t, 6H). MS(m/z): 388[MH]⁺. 5-1-32-methyl-4- cyanophenyl CH₃

H NMR(¹H, CDCl₃): δ 7.70(d, 1H), 7.56(d, 1H), 7.43(dd, 1H), 6.60 (s,1H), 4.54(m, 1H), 3.91(t, 2H), 3.16(t, 2H), 2.53(s, 3H), 2.29(s, 3H),1.79(m, 4H), 0.84 (t, 6H). MS(m/z): 360[MH]⁺. 5-1-4 2-chloro-4-cyanophenyl CH₃

H NMR(¹H, CDCl₃): δ 7.80(d, 1H), 7.73(d, 1H), 7.63(dd, 1H), 6.62 (s,1H), 4.51(m, 1H), 3.92(t, 2H), 3.18(t, 2H), 2.55(s, 3H), 1.79(m, 4H),1.25(m, 4H), 0.88 MS(m/z): 408[MH]⁺. 5-1-5 2-chloro-4- cyanophenyl CH₃

H NMR(¹H, CDCl₃): δ 7.80(d, 1H), 7.73(d, 1H), 7.63(dd, 1H), 6.62 (s,1H), 4.51(m, 1H), 3.92(t, 2H), 3.18(t, 2H), 2.55(s, 3H), 1.79(m, 4H),0.88(t, 6H). MS(m/z): 380[MH]⁺. 6-1-6 2,4-bistrifluoro- methylphenyl CH₃

H NMR(¹H, CDCl₃): δ 9.92(d, 1H), 8.03(d, 1H), 7.69(dd, 1H), 6.62 (s,1H), 4.58(m, 1H), 3.81(t, 2H), 3.18(t, 2H), 2.51(s, 3H), 1.92(m, 4H),0.83(t, 6H). MS(m/Z): 457[MH]⁺.

Example 6 Synthesis of Representative Compounds of Structure (XIb)

[0215]

[0216] Intermediate 20

4-Chloro-3-(2-methoxy-vinyl)-6-methyl-1-(1-propyl-butyl)-1H-pyrrolo[3,2-c]pyridine

[0217] To a solution of (methoxymethyl)-triphenylphosphonium chloride(70 mg, 3 eq) in anh. THF (1 mL), at 0° C., under N₂, BuLi 1.6M in THF(128 μL, 3 eq) was added dropwise. The resulting red reaction mixturewas stirred at 0° C. for 10 min and further 20 min at r.t. Then thereaction mixture was cooled at 0° C. and a solution of4-chloro-6-methyl-1-(1-propyl-butyl)-1H-pyrrolo[3,2]pyridine-3-carbaldehyde(prepared following procedures reported in J. Heterocyclic Chem.; 1996,33, 303; J. Heterocyclic Chem.; 1992, 29, 359; Heterocycles; 2000, 53,11, 2415; Tetrahedron; 1985, 41, 10, 1945. analytical data: NMR (¹H,DMSO): δ 8.49 (s, 1H), 7.70 (s, 1H), 10.4 (s, 1H), 2.53 (s, 3H), 4.57(m, 1H), 1.92/1.79 (m/m 4H), 1.70/0.90 (m/m 4H), 0.77 (t, 6H); MS (m/z):293 [MH]⁺) (20 mg, 0.068 mmol) in anh. THF (1 mL) was added dropwise.

[0218] The reaction mixture was stirred at r.t. for 1 hr. Then water (3mL) was added and the product was extracted with EtOAc (3×5 mL). Thecombined organic layers were washed with sat.aq. NaCl (1×5 mL) and driedover anh. Na₂SO₄. The solids were filtered and the solvent evaporated togive a crude product, which was purified by flash chromatography (silicagel, cHex/EtOAc 95:05). Intermediate 20 was obtained as a yellow oil (15mg, 0.046 mmol, 70%)

[0219] NMR (¹H, CDCl₃): δ (trans) 6.98 (s, 1H), 2.59 (s, 3H), 6.69, (s,1H), 6.81 (d, 1H), 6.40 (d, 1H), 4.21 (m, 1H), 1.82 (m, 4H), 1.53 (m,4H), 0.85 (dt, 6H), 3.83 (s, 3H0; (cis) 6.94 (s, 1H), 2.59 (s, 3H),7.62, (s, 1H), 4.21 (m, 1H), 1.82 (m, 4H), 1.53 (m, 4H), 0.85 (dt, 6H),6.19 (d, 1H), 6.30 (d, 1H), 3.72 (s, 3H), MS (m/z): 321 [MH]⁺.

[0220] Intermediate 21

[4-Chloro-6-methyl-1-(1-propyl-butyl)-1H-pyrrolo[3,2-c]pyridin-3yl]-acetaldehyde

[0221] To a solution of intermediate 20 (85 mg, 0.26 mmol) in anh. THF(2 mL) at 0° C., under N₂, HCl 2N (2 mL) was added dropwise. Theresulting yellow reaction mixture was stirred at 70° C. for 1.5 hr. Thensat.aq. NaHCO₃ (1mL) was added and the product was extracted with EtOAc(3×5 mL). The combined organic layers were washed with sataq. NaCl (1×5mL) and dried over anh. Na₂SO₄. The solids were filtered and the solventevaporated to give a crude product, which was purified by flashchromatography (silica gel, cHex/EtOAc 8:2). Intermediate 21 wasobtained as a yellow oil (55 mg, 0.179 mmol, 70%)

[0222] NMR (¹H, CDCl₃): δ 9.85 (s, 1H), 7.07 (s, 1H), 7.01, (s, 1H),4.21 (m, 1H), 4.04 (s, 2H), 2.60 (s, 3H), 1.82 (m, 4H), 1.16 (m, 4H),0.85 (dt, 6H). MS (m/z): 307 [MH]⁺.

[0223] Intermediate 22

[4-Chloro-6-methyl-1-(1-propyl-butyl)1H-pyrrolo[3,2-c]pyridin-3-yl]ethanol

[0224] To a solution of intermediate 21 (53 mg, 0.173 mmol) in anh. MeOH(4 mL) at 0° C., under N₂, NaBH₄ (13.1 mg, 2 eq) was added. The reactionmixture was stirred at 0° C. for 1 hr. Then water (1 mL) was added andthe product was extracted with EtOAc (3×5 mL). The combined organiclayers were washed with sat.aq. NaCl (1×5 mL) and dried over anh.Na₂SO₄. The solids were filtered and the solvent evaporated to give acrude product, which was purified by flash chromatography (silica gel,cHex/EtOAc 7:3). Intermediate 22 was obtained as a yellow oil (49.8 mg,0.161 mmol, 93%)

[0225] NMR (¹H, DMSO): δ 7.37 (s, 1H), 7.33, (s, 1H), 4.63 (t, 1H), 3.64(t, 2H), 3.01 (t, 2H), 2.44 (s, 3H), 1.77 (m, 4H), 0.89-1.79 (m, 4H),0.77 (t, 6H). MS (m/z): 309 [MH]⁺.

[0226] Intermediate 23

3-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-4-chloro-6-methyl-1-(1-propyl-butyl)-1H-pyrrolo[3,2-c]pyridine

[0227] To a solution of intermediate 22 (49.8 mg, 0.173 mmol) in anh.DMF (2 mL) at 0° C., under N₂, imidazole (110 mg, 10 eq), TBSCl (67 mg,2.8 eq), DMAP (2 mg, 0.1 eq) were added. The reaction mixture wasstirred at r.t. overnight. Then water (1 mL) was added and the productwas extracted with Et₂O (3×5 mL). The combined organic layers werewashed with sataq. NaCl (1×5 mL) and dried over anh. Na₂SO₄. The solidswere filtered and the solvent evaporated to give a crude product, whichwas purified by flash chromatography (silica gel, cHex/EtOAc 9:1).Intermediate 23 was obtained as a yellow oil (65 mg, 0.154 mmol, 95%).

[0228] NMR (¹H, DMSO): δ 6.95 (s/s, 1/1H), 4.17 (m, 1H), 3.91 (t, 2H),3.16 (t, 2H), 2.58 (s, 3H), 1.80 (m, 4H), 1.14-1.05 (m/m, 4H), 0.88 (s,9H), 0.85 (t, 6H), 0.00 (s, 6H). MS (m/z): 423 [MH]⁺.

[0229] Intermediate 24

(2,4-Bis-trifuoromethyl-phenyl)-[3-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-6-methyl-1-(1-propyl-butyl)-1H-pyrrolo[3,2-c]pyridin-4-yl]-amine

[0230] To a mixture of tris(dibenzylideneacetone)palladium(0) (3.7 mg,0.1 eq), 2-(dicyclohexylphosphino)-2′-methylbiphenyl (4.4 mg, 0.3 eq),K₃PO₄ (23 mg, 2.8 eq) a solution of intermediate 23 (17 mg, 0.04 mmol)and 2,4-bis(trifluoromethyl)anilin (18 mg, 2 eq) in anh. DME (1 mL) atr.t., under N₂, was added (crimp cap microwave vial). The reactionmixture was irradiated in CEM Focused Microwave Synthesis System (ModelDiscovery), at 100° C., 150 W, 60 Psi for 20 min (cooling on). Thenwater (1 mL) was added and the product was extracted with Et₂O (3×5 mL).The combined organic layers were washed with sataq. NaCl (1×5 mL) anddried over anh. Na₂SO₄. The solids were filtered and the solventevaporated to give a crude product, which was purified by flashchromatography (silica gel, cHex/EtOAc 95:05). Intermediate 24 wasobtained as a yellow oil (21.5 mg, 0.035 mmol, 88%).

[0231] NMR (¹H, DMSO): δ 7.83 (d, 1H), 7.79 (dd, 1H), 8.16 (d, 1H), 8.23(s, 1), 7.22 (s, 1H), 7.16 (s, 1H), 2.43 (s, 3H), 4.35 (m, 1H), 3.77 (t,2H), 2.94 (t, 2H), 1.8 (m, 4H), 1.15, 0.95(m/m, 4H), 0.79 (t; 6H), 0.68(s, 9H), −0.31 (s, 6H). MS (m/z): 616 [MH]⁺.

[0232] Intermediate 25

2-[4-(2,4-Bis-trifluoromethyl-phenyl)-6-methyl-1-(1-propyl-butyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]-ethanol

[0233] To a solution of intermediate 24 (60 mg, 0.097 mmol) in dry D (5mL) at r.t. Et₃N.3HF (133.6 μL, 8.4 eq) was added. The reaction mixturewas stirred at r.t. overnight. Then water (2 mL) was added and theproduct was extracted with EtOAc (3×5 mL). The combined organic layerswere washed with sat.aq. NaCl (1×5 mL) and dried over anh. Na₂SO₄. Thesolids were filtered and the solvent evaporated to give a crude product,which was purified by flash chromatography (silica gel, cHex/EtOAc 9:1).Intermediate 25 was obtained as a white solid (24.4 mg, 0.048 mmol,50%).

[0234] NMR (¹H, DMSO): δ 9.01 (sa, 1H), 8.07 (d, 1H), 7.81 (s, 1H), 7.76(dd, 1H), 7.19 (s, 1H), 7.10 (s, 1H), 5.19 (sa, 1H), 4.35 (m, 1H), 3.63(m, 2H), 2.88 (m, 2H), 2.38 (s, 3H), 1.85-1.65 (m, 4H), 1.20,0.90 (m,4H), 0.80 (m, 6H). MS (m/z): 502 [MH]⁺.

Example 6-1-15-(2,4-Bis-trifluoromethyl-phenyl)-7-methyl-1-(1-propyl-butyl)-1,3,4,5-tetrahydro-1,5,6-triaza-acenaphthylene

[0235] To a solution of intermediate 25 (23.4 mg, 0.04 mmol) in dryCH₂Cl₂ (2 mL) at r.t. Et₃N (13.5 μL, 2 eq) and MsCl (6.16 μL, 2 eq) wereadded. The reaction mixture was stirred at r.t. for 2 hr. Then water (2mL) was added and the product was extracted with CH₂Cl₂ (3×5 mL). Thecombined organic layers were washed with sat.aq. NaCl (1×5 mL) and driedover anh. Na₂SO₄. The solids were filtered and the solvent evaporated togive a crude product, which was purified by flash chromatography (silicagel, cHex/EtOAc 9:1). Example 6-1-1 was obtained as a yellow oil (6 mg,0.012 mmol, 31%).

[0236] All the analytical data are set forth in the following Table 1.TABLE 1 (XIb)

R₈, Cpd. R₃, R₅, No. R₁ R₂ R_(4″) R_(6″) Analitycal Data 6-1-12,4-bistrifluoro- methylphenyl CH₃

H NMR(¹H, DMSO): δ 8.08(dd, 1H), 8.03(s, 1H), 7.81(d, 1H), 6.87(s, 1H),6.61(s, 1H), 4.19 (m, 1H), 3.72(t, 2H), 3.02(t, 2H), 2.19(s, 3H),1.80-1.70(m, 4H), 1.30-1.10(m, 4H), 0.79(m, 6H). MS(m/z): 483 [MH]⁺.

Example 7 CRF Receptor Binding Activity

[0237] The compounds of this invention may be evaluated for bindingactivity to the CRF receptor by a standard radioligand binding assay asgenerally described by DeSouza et al. (J. Neurosci. 7:88-100, 1987). Byutilizing various radiolabeled CRF ligands, the assay may be used toevaluate the binding activity of the compounds of the present inventionwith any CRF receptor subtype. Briefly, the binding assay involves thedisplacement of a radiolabeled CRF ligand from the CRF receptor.

[0238] More specifically, the binding assay is performed in 1.5 mLEppendorf tubes using approximately 1×10⁶ cells per tube stablytransfected with human CRF receptors. Each tube receives about 0.1 mL ofassay buffer (eg., Dulbecco's phosphate buffered saline, 10 mM magnesiumchloride, 20 μM bacitracin) with or without unlabeled sauvagine,urotensin I or CRF (final concentration, 1 μM) to determine nonspecificbinding, 0.1 ml of [¹²⁵I] tyrosine—ovine CRF (final concentration ˜200pM or approximately the K_(D) as determined by Scatchard analysis) and0.1 mL of a membrane suspension of cells containing the CRF receptor.The mixture is incubated for 2 hours at 22° C. followed by theseparation of the bound and free radioligand by centrifugation.Following two washes of the pellets, the tubes are cut just above thepellet and monitored in a gamma counter for radioactivity atapproximately 80% efficiency. All radioligand binding data may beanalyzed using the nonlinear least-square curve-fitting program LIGANDof Munson and Rodbard (Anal. Biochem. 107:220, 1990).

Example 8 CRF-Stimulated Adenylate Cyclase Activity

[0239] The compounds of the present invention may also be evaluated byvarious functional testing. For example, the compounds of the presentinvention may be screened for CRF-stimulated adenylate cyclase activity.An assay for the determination of CRF-stimulated adenylate cyclaseactivity may be performed as generally described by Battaglia et al.(Synapse 1:572, 1987), with modifications to adapt the assay to wholecell preparations. More specifically, the standard assay mixture maycontain the following in a final volume of 0.5 mL: 2 mM L-glutamine, 20mM HEPES, and 1 mM IMBX in DMEM buffer. In stimulation studies, wholecells with the transfected CRF receptors are plated in 24-well platesand incubated for 1 h at 37° C. with various concentrations ofCRF-related and unrelated peptides in order to establish thepharmacological rank-order profile of the particular receptor subtype.Following the incubation, the media is aspirated, the wells rinsed oncegently with fresh media, and the media aspirated. To determine theamount of intracellular cAMP, 300 μl of a solution of 95% ethanol and 20mM aqueous hydrochloric acid is added to each well and the resultingsuspensions are incubated at −20° C. for 16 to 18 hours. The solution isremoved into 1.5 mL Eppendorf tubes and the wells washed with anadditional 200 μl of ethanol/aqueous hydrochloric acid and pooled withthe first fraction. The samples are lyophilized and then resuspendedwith 500 μl sodium acetate buffer. The measurement of cAMP in thesamples is performed using a single antibody kit from BiomedicalTechnologies Inc. (Stoughton, Mass.). For the functional assessment ofthe compounds, a single concentration of CRF or related peptides causing80% stimulation of cAMP production is incubated along with variousconcentrations of competing compounds (10⁻¹² to 10⁻⁶ M).

[0240] It will be appreciated that, although specific embodiments of theinvention have been described herein for purposes of illustration,various modifications may be made without departing from the spirit andscope of the invention.

[0241] Accordingly, the invention is not limited except as by theappended claims.

What is claimed is:
 1. A compound having the following structure:

or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof,wherein: A is a bond or C=(Z); X is nitrogen or CR₃; Y is —N═, —N(R₇)—,—C(R₈)═ or —O—; Z is O, S or NR₉; R₁ is alkyl, substituted alkyl, aryl,substituted aryl, heteroaryl, or substituted heteroaryl; R₂ is hydrogen,alkyl, substituted alkyl, alkoxy, thioalkyl, halo, cyano, haloalkyl; R₃is hydrogen, alkyl, substituted alkyl, halo or haloalkyl; R₄ ishydrogen, alkyl, substituted alkyl, C(O)R₁, aryl, substituted aryl,heterocycle or substituted heterocycle; R₅ is hydrogen, halogen, alkyl,substituted alkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, alkoxy, thioalkyl, C(O)R₁, NR₁₀R₁₁ or cyano; R₆ is hydrogen,halogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, alkoxy, thioalkyl, C(O)R₁, NR₁₀R₁₁ or cyano; R₇is hydrogen, alkyl, substituted alkyl, C(O)R₁, aryl, substituted aryl,heteroaryl, or substituted heteroaryl; R₈ is hydrogen, halogen, alkyl,substituted alkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, alkoxy, thioalkyl, C(O)alkyl, NR₁₀R₁₁ or cyano; R₉ ishydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,or substituted heteroaryl; and R₁₀, R₁₁ are the same or different andare independently hydrogen, alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl.
 2. The compound of claim 1wherein X is CR₃.
 3. The compound of claim 1 wherein X is nitrogen. 4.The compound of claim 1 having the following structure:

wherein R₁ is alkyl, substituted alkyl, aryl, substituted aryl,heteroaryl, or substituted heteroaryl; R₂ is hydrogen, alkyl,substituted alkyl, alkoxy, thioalkyl, halo, cyano, haloalkyl; R₃ ishydrogen, alkyl, substituted alkyl, halo or haloalkyl; R₄ is hydrogen,alkyl, substituted alkyl, C(O)R₁, aryl, substituted aryl, heterocycle orsubstituted heterocycle; R₅ is hydrogen, halogen, alkyl, substitutedalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,alkoxy, thioalkyl, C(O)R₁, NR₁₀R₁₁ or cyano; R₆ is hydrogen, halogen,alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, alkoxy, thioalkyl, C(O)R₁, NR₁₀R₁₁ or cyano; R₇is hydrogen, alkyl, substituted alkyl, C(O)R₁, aryl, substituted aryl,heteroaryl, or substituted heteroaryl; R₈ is hydrogen, halogen, alkyl,substituted alkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, alkoxy, thioalkyl, C(O)alkyl, NR₁₀R₁₁ or cyano; and R₁₀, R₁₁are the same or different and are independently hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl.
 5. The compound of claim 1 having the following structure:

wherein R₁ is alkyl, substituted alkyl, aryl, substituted aryl,heteroaryl, or substituted heteroaryl; R₂ is hydrogen, alkyl,substituted alkyl, alkoxy, thioalkyl, halo, cyano, haloalkyl; R₃ ishydrogen, alkyl, substituted alkyl, halo or haloalkyl; R₄ is hydrogen,alkyl, substituted alkyl, C(O)R₁, aryl, substituted aryl, heterocycle orsubstituted heterocycle; R₅ is hydrogen, halogen, alkyl, substitutedalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,alkoxy, thioalkyl, C(O)R₁, NR₁₀R₁₁ or cyano; R₆ is hydrogen, halogen,alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, alkoxy, thioalkyl, C(O)R₁, NR₁₀R₁₁ or cyano; R₈is hydrogen, halogen, alkyl, substituted alkyl, aryl, substituted aryl,heteroaryl, substituted heteroaryl, alkoxy, thioalkyl, C(O)alkyl,NR₁₀R₁₁ or cyano; and R₁₀, R₁₁ are the same or different and areindependently hydrogen, alkyl, substituted alkyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl.
 6. The compound of claim 1selected in a group consisting from:7-methyl-1-(1-propyl-butyl)-5-[4-(1,1,2-trifluoro-ethyl)-2-trifluoromethylphenyl]1,2,2a,3,4,5-exahydro-1,5,6,8-tetraaza-acenaphtylene;3-methyl-4-[7-methyl-1-(1-propyl-butyl)-3,4-dihydro-1H-1,5,6,8-tetraaza-acenaphthylen-5-yl]-benzonitrile;4-[1-(1-ethyl-propyl)-7-methyl-3,4-dihydro-1H-1,5,6,8-tetraaza-acenaphthylen-5-yl]-3-methyl-benzonitrile;3-chloro-4-[7-methyl-1-(1-propyl-butyl)-3,4-dihydro-1H-1,5,6,8-tetraaza-acenaphthylen-5-yl]-benzonitrile;3-chloro-4-[1-(1-ethyl-propyl)-7-methyl-3,4-dihydro-1H-1,5,6,8-tetraaza-acenaphthylen-5-yl]-benzonitrile;5-(2,4-bis-trifluoromethyl-phenyl)-1-(1-ethyl-propyl)-7-methyl-1,3,4,5-tetrahydro-1,5,6,8-tetraaza-acenaphthylene;5-(2,4-bis-trifluoromethyl-phenyl)-7-methyl-1-(1-propyl-butyl)-1,3,4,5-tetrahydro-1,5,6-triaza-acenaphthylene.7. A composition comprising a compound of claim 1 in combination with apharmaceutically acceptable carrier or diluent.
 8. A method for treatinga disorder manifesting hypersecretion of CRF in a warm-blooded animal,comprising administering to the animal an effective amount of thepharmaceutical composition of claim
 4. 9. The method of claim 5 whereinthe disorder is stroke.
 10. The method of claim 5 wherein the disorderis depression.
 11. The method of claim 5 wherein the disorder isanxiety.
 12. The method of claim 5 wherein the disorder is irritablebowel syndrome (IBS).
 13. The method of claim 5 wherein the disorder isinflammatory bowel disease (IBD).